Two of the benzodiazepines, chlordiazepoxide (Librium, CDP) and diazepam (Valium; DZP), are among the most widely prescribed drugs in the United States. Alcohol is often used in combination with these drugs, but very little is known about the long-lasting biochemical and clinical consequences of their combined use. It has been pointed out that the use of benzodiazepines in the treatment of alcoholism beyond detoxification is among the most common mistakes made by physicians; this is because these drugs are not only ineffective in alcoholism treatment, but are contraindicated due to the serious addiction potential and synergism with alcohol. Therefore, it is highly desirable and clinically relevant to learn about the long-term effects of combined ethanol/benzodiazepine intake. Animal models are needed to circumvent the ethical and humane considerations which dictate against intensive studies on combined drug dependence in man. This application aims to test the following hypothesis: (a) CDP is cross-tolerant to ethanol and vice versa, (b) cross-dependence between ethanol and CDP can occur; (c) the pharmacodynamic interactions resulting from chronic ethanol/CDP intake produce changes different from those elicited by either drug alone. Therefore, the following investigations are proposed: (1) development of a mouse model of physical dependence on CDP (and other benzodiazepines); the drug is incorporated into a liquid diet which serves as the sole source of food and fluid; (2) assessment of the time course of development and the degree of tolerance to CDP by behavioral, biochemical, and pharmacological measurements; (3) investigation of the cross-tolerance between CDP and ethanol in mice made physically dependent on ethanol or CDP; (4) determination of whether ethanol can substitute for CDP after CDP dependence or vice versa; (5) development of a mouse model for alcohol/CDP dependence and examination of the accompanying long-term effects such as tolerance and withdrawal reactions. A better understanding of the pharmacodynamic interactions between the benzodiazepines and ethanol is necessary for the better prevention and treatment of the combined drug abuse problems.